Canonical and Non-Canonical Activation of NLRP3 Inflammasome at the Crossroad between Immune Tolerance and Intestinal Inflammation

Abstract

Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in regulating the integrity of intestinal homeostasis and shaping innate immune responses during bowel inflammation. Intensive research efforts are being made to achieve an integrated view about the protective/detrimental role of canonical and non-canonical NLRP3 inflammasome activation in the maintenance of intestinal microenvironment integrity. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome could represent a promising molecular target for the therapeutic management of inflammatory immune-mediated gut diseases. The present review has been intended to provide a critical appraisal of the available knowledge about the role of canonical and non-canonical NLRP3 inflammasome activation in the dynamic interplay between microbiota, intestinal epithelium, and innate immune system, taken together as a whole integrated network regulating the maintenance/breakdown of intestinal homeostasis. Moreover, special attention has been paid to the pharmacological modulation of NLRP3 inflammasome, emphasizing the concept that this multiprotein complex could represent a suitable target for the management of inflammatory bowel diseases.

Keywords: NLRP3; bowel inflammation; canonical; enteric microbiota; immune system; intestinal homeostasis; non-canonical.

Figure 1

Mechanisms of canonical and non-canonical NLRP3 inflammasome activation. Diagram showing the canonical and non-canonical NLRP3 inflammasome activation, and representation of the molecular mechanisms through which several compounds inhibit NLRP3 activation and counteract intestinal inflammation. Left panel: first step of canonical NLRP3 inflammasome activation by TLRs–MyD88 and/or TNFR, which activate pro-IL-1β and NLRP3 transcription via NF-κB activation. The second step results in NLRP3 inflammasome oligomerization, leading to caspase-1 activation as well as IL-1β and IL-18 release. Extracellular ATP, degradation of extracellular matrix components, increase in potassium efflux, ROS, cathepsin activation, and deubiquitination promote NLRP3 inflammasome oligomerization and activation. Caspase-1 activation promotes also pyroptosis and HMGB1 release. Right panel: first step of non-canonical NLRP3 inflammasome activation. Gram-negative bacteria (i.e., Citrobacter rodentium, Escherichia coli, and Vibrio cholerae) activate the TLR4–MyD88 and TRIF pathways, with consequent nuclear translocation of NF-κB, which promotes the transcription of IL-1β, IL-18, and NLRP3 as well as IRF-3 and IRF7 genes. The IRF3–IRF7 complex (1) elicits the expression of IFN-α/β (2) that binds the IFNAR1/IFNAR2 receptor (3), leading to activation of the JAK/STAT pathway (4) and transcription of caspase-11 gene (5). In the second step, unidentified scaffold proteins or receptors induced by Gram-negative bacteria cleave and activate caspase-11, which induces pyroptosis as well as HMGB1 and IL-1α release, and promotes the activation of NLRP3-ASC-caspase-1 pathway. Abbreviations: NLRP3, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3; TLRs, toll-like receptors; MyD88, adaptor molecules myeloid differentiation primary response 88; TNFR, tumor necrosis factor receptor; NF-κB, nuclear factor-κB; ATP, adenosine triphosphate, ROS, reactive oxygen species; HMGB1, high mobility group box 1; TRIF, toll/IL-1 receptor homology (TIR)-domain-containing adapter-inducing interferon-β; IRF, interferon regulatory factor; IFN, interferon; IFNAR, interferon-α/β receptor; IL, interleukin; P2X, purinergic receptor 7; JAK/STAT, janus kinase/signal transducers and activators of transcription; NRF2/ARE, nuclear factor (erythroid-derived 2)-like 2/antioxidant response element.

Figure 2

Canonical and non-canonical activation of nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome pathways in intestinal homeostasis and inflammation. Diagram showing the role of canonical and non-canonical activation of NLRP3 inflammasome pathways in intestinal homeostasis and inflammation. Left panel: Canonical and non-canonical NLRP3 inflammasome activation in intestinal homeostasis. Canonical NLRP3 inflammasome activation plays a key role in the maintenance of the integrity of intestinal epithelial barrier as well as in the enteric microbiota composition through the release of IL-18 by macrophages and intestinal epithelial cells, the regulation of crypt bactericidal capacity, and the release of colonic β-defensin by macrophages. Likewise, non-canonical NLRP3 inflammasome activation contributes to maintain the integrity of intestinal epithelial barrier through IL-18 release by macrophages and intestinal epithelial cells. In addition, caspase-11 contributes, in a NLRP3-independent manner, to the maintenance of intestinal homeostasis promoting the release of Il-1α and IL-22. Right panel: Canonical and non-canonical NLRP3 inflammasome activation in intestinal inflammation. In the acute phase of inflammation, canonical NLRP3 inflammasome activation promotes the release of IL-1β and IL-18, contributing to tissue repair and maintenance of epithelial barrier integrity. Conversely, in the chronic phase of inflammation, canonical NLRP3 inflammasome overactivation is associated with an increase in IL-1β and IL-18 release that is harmful to the host. In addition, IL-1β and IL-18 release induce the differentiation of T cells into pathogenic Th1 and Th17 phenotypes, which contribute to sustain the inflammatory response. Non-canonical NLRP3 inflammasome activation plays a protective role during bowel inflammation likely via IL-18 release that stimulates intestinal epithelial cell proliferation and barrier repair. In addition, the release of IL-22 and IL-1α contributes to the repair of intestinal epithelial barrier. However, caspase-11 contributes also to promote intestinal epithelial cell proliferation and barrier repair by recruitment of yet unidentified inflammasome-independent pathways.